Nucleophilic Substitution Reactions of Epoxides

Draw the major products obtained from heating each of the following ethers with one equiva- 

Solution to 23a The reaction takes place hy an 8 2 pathway because neither alkyl group will form a relatively stable carbocation (one would be vinylic and the other primary). Iodide ion attacks the carbon of the ethyl group because otherwise it would have to attack a vinylic carbon, and vinylic carbons are not attacked by nucleophiles (Section 9.5). Thus, the major products are ethyl iodide and an enol that immediately rearranges to an aldehyde (Section 7.7). 

We have seen that an aUcene can be converted into an epoxide, a three-membered ring ether, by a peroxyacid (Section 6.10). 

An alkene can also be converted into an epoxide by the addition of HOCl (by using CI2 and H2O) followed by reaction with NaH (Sections 6.9 and 10.10). 

The reaction coordinate diagrams for nucleophilic attack of hydroxide ion on ethylene oxide and on diethyl ether. The greater reactivity of the epoxide is a result of the strain in the three-membered ring, which increases the epoxide s free energy. 

---

Nucleophilic substitution reactions of epoxides (Section 11.7). The mechanisms are shown on pages 506 and 507. 

The normal pathway toward excretion of foreign molecules like aflatoxin Bi and dibenzo [a,/]pyrene, however, also involves nucleophilic substitution reactions of their epoxides. 

Epoxides are important intermediates in many industrial processes. For example, the reaction of the simplest epoxide, ethylene oxide, with water is employed to produce ethylene glycol, which is used in antifreeze and to prepare polymers such as Dacron. One method for the preparation of ethylene oxide employs an intramolecular nucleophilic substitution reaction of ethylene chlorohydrin ... 

Fpr most substitution reactions of epoxides, then, regioselectivity is much higher if you give in to the epoxide s desire to open at the less substituted end, and enhance it with a strong nucleophile under basic conditions. 

Palladium-catalyzed nucleophilic substitution reactions of allylic substrates have become useful in organic synthesis. As allylic substrates, allyl alcohols, halides, carboxylates, phosphates or vinyl epoxides can be utilized. 

Lithium n butyl (phenylthio) cuprate has been used in nucleophilic substitution reactions of arenesulfonyl fluorides, al-lylic acetates, 9 BBN, propargyllc carbamates, and bromo-alkenes, as well as in nucleophilic additions to acetoxy-epoxides. It Is a good choice for 1,4-addItIon of an n-Bu group, having been used in 1,4 addition-elimination reactions of a-oxoketene dithloacetals and 3-halo-2-cycloalkenones, and in tandem vicinal dialkylation reactions of 5-methyleneoxa-zolones and alkynes. A typical example Is the use of the reagentin the stereospecific synthesis of (, -2-heptenoicacidfrom acetylene (eq 1). ... 

The synthetic route of sulfite-linked cycloaliphatic epoxy resin is presented in Figure 8.13 [38]. The synthesis of intermediate is achieved via the nucleophilic substitution reaction of thionyl chloride with cyclohex-3-enyl-1-methanol. Subsequently, Epo-S is obtained by epoxidation with OXONE oxidant. Epo-S is liquid at room temperature which is favorable for the underfilling encapsulation for high-density electronic packaging technologies such as flip chip plastic ball grid array (FC-PBGA) and MCM. 

Overall the stereospecificity of this method is the same as that observed m per oxy acid oxidation of alkenes Substituents that are cis to each other m the alkene remain CIS m the epoxide This is because formation of the bromohydrm involves anti addition and the ensuing intramolecular nucleophilic substitution reaction takes place with mver Sion of configuration at the carbon that bears the halide leaving group... 

There is an important difference in the regiochemistry of ring opening reactions of epoxides depending on the reaction conditions Unsymmetncally substituted epoxides tend to react with anionic nucleophiles at the less hindered carbon of the ring Under conditions of acid catalysis however the more highly substituted carbon is attacked... 

As we ve just seen nucleophilic ring opening of ethylene oxide yields 2 substituted derivatives of ethanol Those reactions involved nucleophilic attack on the carbon of the ring under neutral or basic conditions Other nucleophilic ring openings of epoxides like wise give 2 substituted derivatives of ethanol but either involve an acid as a reactant or occur under conditions of acid catalysis... 

Nucleophilic ring opening of epoxides has many of the features of an Sn2 reaction. Inversion of configuration is observed at the carbon at which substitution occurs. 

An a ,/3-epoxycarboxylic ester (also called glycidic ester) 3 is formed upon reaction of a a-halo ester 2 with an aldehyde or ketone 1 in the presence of a base such as sodium ethoxide or sodium amide. Mechanistically it is a Knoevenagel-type reaction of the aldehyde or ketone 1 with the deprotonated a-halo ester to the a-halo alkoxide 4, followed by an intramolecular nucleophilic substitution reaction to give the epoxide 3 ... 

Sn2 substitution reactions of alkyl halides with hard nucleophiles such as alkyl anions can be achieved most readily with the aid of organocopper chemistry [95]. Sn2 reactions with epoxides and aziridines are also synthetically useful [96]. The... 

The arene oxide valence tautomer of oxepins in principle should undergo nucleophilic substitution reactions (Sn2) which are characteristic of simple epoxides. In reality oxepin-benzene oxide (7) is resistant to attack by hard nucleophiles such as OH-, H20, NH2- and RNH2. Attempts to obtain quantitative data on the relative rates of attack of nucleophiles on (7) in aqueous solution hqye been thwarted by competition from the dominant aromatization reaction. 

Epoxides are much more reactive than simple ethers due to ring strain, and are useful intermediates because of their chemical versatility. They undergo nucleophilic substitution reactions with both acids and bases to produce alcohols (see Sections 4.3.7 and 5.5.4). 

A nucleophile is an electron rich species that reacts with an electrophile. The term electrophile literally means electron-loving , and is an electron-deficient species that can accept an electron pair. A number of nucleophilic substitution reactions can occur with alkyl halides, alcohols and epoxides. However, it can also take place with carboxylic acid derivatives, and is called nucleophilic acyl substitution. 

---